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Exploiting the synergy between computational and experimental biophysics for efficient cancer drug development 利用计算和实验生物物理学之间的协同作用,有效地开发癌症药物
Pub Date : 2025-12-10 DOI: 10.1016/j.ejmcr.2025.100320
Ana Álvarez-Mena , Mélanie Berbon , Carmelo Di Primo , Rebeca Garcia-Fandino , Ángel Piñeiro , Carlos Fernandez-Lozano , Hugo A.L. Filipe , Birgit Habenstein
Targeted cancer therapies have revolutionized oncology by developing treatments that specifically target cancer cells, reducing side effects. However, traditional drug discovery approaches are often hindered by high costs, long timelines, and low success rates. To address these challenges, the combination of computational and experimental biophysical techniques has become a highly effective approach. Molecular modeling methods, such as docking, molecular dynamics simulations, and virtual screening, enable in silico identification and optimization of drug candidates, while experimental biophysical techniques like NMR, SPR, and BLI validate molecular structures, binding interactions and affinities. This combined approach enhances the precision and efficiency of drug discovery, enabling progress in targeting oncogenic mutations, disrupting protein-protein interactions, and advancing drug repurposing efforts. Despite its potential, several challenges remain, including predictive limitations in computational models, experimental reproducibility, and the complexity of integrating diverse datasets. Future advances, particularly in artificial intelligence-driven methodologies, high-throughput screening, and drug repurposing, hold great potential to accelerate the development of innovative and effective cancer therapies.
靶向癌症治疗通过开发专门针对癌细胞的治疗方法,减少了副作用,从而彻底改变了肿瘤学。然而,传统的药物发现方法往往受到高成本、长时间和低成功率的阻碍。为了应对这些挑战,计算和实验生物物理技术的结合已经成为一种非常有效的方法。分子建模方法,如对接、分子动力学模拟和虚拟筛选,可以在计算机上识别和优化候选药物,而实验生物物理技术,如NMR、SPR和BLI,可以验证分子结构、结合相互作用和亲和力。这种联合方法提高了药物发现的准确性和效率,使靶向致癌突变、破坏蛋白质-蛋白质相互作用和推进药物重新利用的努力取得进展。尽管其潜力巨大,但仍存在一些挑战,包括计算模型的预测局限性、实验可重复性以及整合不同数据集的复杂性。未来的进展,特别是在人工智能驱动的方法、高通量筛选和药物再利用方面,具有加速创新和有效癌症治疗发展的巨大潜力。
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引用次数: 0
Inhibition of ginsenoside Re on pulmonary fibrosis induced by bleomycin in mice: Involved in modulating the CX3CL1/CX3CR1 axis 人参皂苷Re对博来霉素诱导小鼠肺纤维化的抑制作用:参与调节CX3CL1/CX3CR1轴
Pub Date : 2025-12-06 DOI: 10.1016/j.ejmcr.2025.100319
Zhaoqin Wen , Huiyun Yang , Hong Ling , Huicai Lin , Xiaoyan Chen , Wan-Lan Shi , Yongxiang Song , Jiang Deng
Pulmonary fibrosis (PF) is a common pathological feature of a variety of diffuse, progressive and irreversible pulmonary interstitial diseases, and effective therapeutic agents are currently lacking. Our previous study found that the total ginsenosides can improve pulmonary fibrosis induced by bleomycin in mice. Ginsenosides Re (G-Re) is one of the most abundant active ingredients in total ginsenosides and has a variety of pharmacological activities. This study investigated the inhibitory effect and mechanism of Re on pulmonary fibrosis in mice induced by bleomycin. The effects of G-Re on pulmonary fibrosis were evaluated using lung function measurement, pathological analysis, and detection of deposition of extracellular matrix (ECM). To investigate the mechanisms underlying the anti-pulmonary fibrosis effects of G-Re, chemokine CX3C ligand 1 (CX3CL1) and receptor 1 (CX3CR1), transforming growth factor beta 1 (TGF-β1), mitogen-activated protein kinase 1/2 (MEK1/2), extracellular signal-regulated kinase1/2 (ERK1/2), matrix metalloproteinase 2 (MMP2), and tissue inhibitor of metalloproteinases-1 (TIMP-1) in lung tissues were detected by molecular biology techniques, immunofluorescence and immunohistochemistry. Treatment with G-Re ameliorated pulmonary fibrosis in mice induced by bleomycin. In addition, it downregulated the levels of CX3CL1, CX3CR1, TGF-β1, MEK1/2, and MMP2. It upregulated the level of TIMP-1. These findings indicate that G-Re exerts protective effects against pulmonary fibrosis, likely through suppression of the CX3CL1/CX3CR1 axis and coordinated regulation of the ERK 1/2 signaling pathway and matrix metalloproteinases (MMPs), leading to reduced alveolar basement membrane injury and diminished extracellular matrix (ECM) accumulation in murine lung tissue.
肺纤维化(Pulmonary fibrosis, PF)是多种弥漫性、进行性和不可逆性肺间质性疾病的共同病理特征,目前缺乏有效的治疗药物。我们前期研究发现人参总皂苷对博来霉素所致小鼠肺纤维化有改善作用。人参皂苷Re (G-Re)是人参总皂苷中含量最丰富的活性成分之一,具有多种药理活性。本研究探讨稀土对博来霉素致小鼠肺纤维化的抑制作用及其机制。通过肺功能测量、病理分析和细胞外基质沉积(ECM)检测来评估G-Re对肺纤维化的影响。为探讨G-Re抗肺纤维化作用的机制,采用分子生物学、免疫荧光和免疫组化技术检测肺组织趋化因子CX3C配体1 (CX3CL1)和受体1 (CX3CR1)、转化生长因子β1 (TGF-β1)、丝裂原活化蛋白激酶1/2 (MEK1/2)、细胞外信号调节激酶1/2 (ERK1/2)、基质金属蛋白酶2 (MMP2)和金属蛋白酶组织抑制剂-1 (TIMP-1)。G-Re治疗可改善博来霉素所致小鼠肺纤维化。下调CX3CL1、CX3CR1、TGF-β1、MEK1/2、MMP2水平。上调TIMP-1水平。这些发现表明,G-Re可能通过抑制CX3CL1/CX3CR1轴和协调调节ERK 1/2信号通路和基质金属蛋白酶(MMPs)对肺纤维化具有保护作用,从而减少肺泡基底膜损伤和减少肺组织中细胞外基质(ECM)的积累。
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引用次数: 0
Sanguinarine alleviates cisplatin-induced apoptosis in AKI by upregulating BCL-2 through targeting the gene promoter i-motif 血桂碱通过靶向基因启动子i基序上调BCL-2,缓解顺铂诱导的AKI细胞凋亡
Pub Date : 2025-12-04 DOI: 10.1016/j.ejmcr.2025.100316
Xiaoya Li , Wen-Li Fu , Fenfen He , Xiaoli Xu , Bianxiang Hu , Yuqing Wang , Shuo-Bin Chen , Jianmin Chen
Acute kidney injury (AKI) is a severe clinical condition with high morbidity and mortality. Apoptosis of renal tubular epithelial cells is a key pathological driver, and upregulation of the anti-apoptotic protein BCL-2 is a validated protective mechanism. The BCL-2 promoter harbors a C-rich sequence capable of forming an i-motif, a non-canonical DNA secondary structure with regulatory functions. Previous studies have reported steroid-like molecules as potential ligands for the BCL-2 i-motif, but their interactions were generally weak and lacked systematic pharmacophore insight. Here, we identify Sanguinarine (SG), a benzophenanthridine alkaloid, as a more potent ligand from a natural product library. Surface plasmon resonance (SPR) revealed broad-spectrum binding of SG to multiple promoter i-motifs, yet circular dichroism (CD) and melting assays suggested a relatively stronger stabilizing effect on the BCL-2 C-rich structure under our assay conditions. This apparent conformational preference, rather than strict binding selectivity, led to transcriptional activation of BCL-2 and protection of HK-2 cells from cisplatin-induced apoptosis. While i-motifs have only rarely been explored in AKI, our study provides new mechanistic insight by defining an aromatic–cationic pharmacophore and suggesting that structure-dependent stabilization may serve as a plausible mechanism for promoter-specific modulation. These findings support the biological relevance of the BCL-2 i-motif and highlight natural products as valuable scaffolds for nucleic-acid–interacting agents in renal injury models.
急性肾损伤(AKI)是一种严重的临床疾病,发病率和死亡率都很高。肾小管上皮细胞的凋亡是一个关键的病理驱动因素,而抗凋亡蛋白BCL-2的上调是一个被证实的保护机制。BCL-2启动子包含一个富含c的序列,能够形成i-motif,这是一个具有调节功能的非规范DNA二级结构。先前的研究报道了类固醇样分子作为BCL-2 i-motif的潜在配体,但它们的相互作用通常很弱,缺乏系统的药效团洞察力。在这里,我们从天然产物库中发现了一种名为血碱(SG)的苯并苯胺生物碱,是一种更有效的配体。表面等离子体共振(SPR)显示SG与多个启动子i基序的广谱结合,而圆二色性(CD)和熔融实验表明,在我们的实验条件下,SG对BCL-2富c结构具有相对较强的稳定作用。这种明显的构象偏好,而不是严格的结合选择性,导致BCL-2的转录激活和保护HK-2细胞免受顺铂诱导的凋亡。虽然i-motif在AKI中很少被探索,但我们的研究通过定义芳香阳离子药效团提供了新的机制见解,并表明结构依赖的稳定化可能是启动子特异性调节的合理机制。这些发现支持了BCL-2 i-motif的生物学相关性,并突出了天然产物作为肾损伤模型中核酸相互作用药物的有价值的支架。
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引用次数: 0
Synthetic developments and biological insights of 1,2,3-triazoles: Unravelling scope for drug discovery 1,2,3-三唑类化合物的合成进展和生物学见解:揭示药物发现的范围
Pub Date : 2025-11-29 DOI: 10.1016/j.ejmcr.2025.100315
Glanish Jude Martis, Sowmya Maiya, Santosh L. Gaonkar
1,2,3-Triazoles have emerged as instrumental heterocyclic scaffolds playing key role in the field of synthetic and medicinal chemistry. The recent advancements utilizing the evolving technologies and the subsequent development of various synthetic strategies have dragged the attention based on their merits when compared to those with classical methods. In this review, different synthetic methods such as metal-catalyzed cycloaddition and metal-free reactions have been discussed with their noteworthy results. Also, focussing on the eco-friendliness domain, reactions following the green principles have been included. The scope of click reactions is wide and their optimisations play a crucial role. Erstwhile, the biological activity of the potential medicinal targets has opened a wide-gateway for the future medicinal chemistry and chemical biology. The impact of potent triazoles in appropriate areas is inclined throughout the review having the coverage of past twelve years which would help researchers working on discovery chemistry and biology across the world.
1,2,3-三唑类化合物作为杂环支架类化合物在合成化学和药物化学领域发挥着重要作用。近年来利用不断发展的技术和随后发展的各种综合策略,由于其与经典方法相比的优点而引起了人们的注意。本文对金属催化环加成和无金属反应等不同的合成方法进行了综述,并取得了令人瞩目的成果。此外,关注生态友好领域,遵循绿色原则的反应也包括在内。点击反应的范围很广,它们的优化起着至关重要的作用。过去,潜在药物靶点的生物活性为未来的药物化学和化学生物学打开了广阔的大门。强效三唑在适当领域的影响在过去12年的回顾中是倾斜的,这将有助于世界各地的研究人员发现化学和生物学。
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引用次数: 0
Nitrofuranyl derivatives as promising antitubercular agents: Structural insights and drug discovery perspectives 硝基呋喃基衍生物作为有前途的抗结核药物:结构见解和药物发现观点
Pub Date : 2025-11-28 DOI: 10.1016/j.ejmcr.2025.100314
Afreen N , Smriti Sharma
The emergence of MDR (multidrug-resistant) and XDR (extensively drug-resistant) variants of Mycobacterium tuberculosis has contributed to the universal resurgence of tuberculosis (TB). Nitrofuran-based compounds, traditionally used as antibacterial agents, have recently gained attention for their potential antitubercular properties. This review presents a comprehensive overview of structural classes of nitrofuran derivatives—including nitrofuranylamides, hydrazides, triazoles, spirocyclic hybrids, and prodrugs—and their corresponding structure–activity relationships, efficacy profiles, and safety evaluations. Several lead compounds exhibit potent in vitro as well as in vivo activity, often surpassing the effectiveness of existing TB drugs while maintaining favorable cytotoxicity and selectivity indices. Repurposing strategies and chemical modifications have significantly improved their pharmacological profiles, offering promising avenues for TB drug discovery. While current findings are encouraging, further mechanistic studies, pharmacokinetic optimization, and translational research are essential to advance nitrofuran derivatives toward clinical application. This review underscores the therapeutic value of nitrofuran scaffolds and supports their continued exploration as viable candidates in the global effort to combat TB.
多药耐药(MDR)和广泛耐药(XDR)结核分枝杆菌变体的出现导致结核病的普遍死灰复燃。硝基呋喃类化合物,传统上被用作抗菌剂,最近因其潜在的抗结核特性而受到关注。本文综述了硝基呋喃衍生物的结构类别,包括硝基呋喃酰胺、肼、三唑、螺环杂化物和前药,以及它们相应的构效关系、疗效概况和安全性评价。一些先导化合物在体外和体内都表现出强大的活性,通常超过现有结核病药物的有效性,同时保持良好的细胞毒性和选择性指数。重新利用策略和化学修饰显著改善了它们的药理学特征,为结核病药物的发现提供了有希望的途径。虽然目前的发现令人鼓舞,但进一步的机制研究、药代动力学优化和转化研究对于推进硝基呋喃衍生物的临床应用至关重要。这篇综述强调了硝基呋喃支架的治疗价值,并支持将其作为全球抗结核努力的可行候选药物继续探索。
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引用次数: 0
Evaluation of the hepatoprotective properties of Vitex Altissima bark extracts and isolated bioactive: In-vitro and In-vivo approach 黄荆树皮提取物和分离生物活性的肝保护特性评价:体外和体内方法
Pub Date : 2025-11-20 DOI: 10.1016/j.ejmcr.2025.100312
I.A. Chethan , Jaishree Vaijanathappa
Vitex altissima (V. altissima), an ethnopharmacologically valuable plant, is explicitly used as traditional medicine by local folks to cure liver-related disorders in Coorg. Hence, the present study aimed to evaluate the bark extract's hepatoprotective and antioxidant mechanisms and its isolated potent compound against CCl4-induced toxicity. Ethanolic bark extracts underwent phytochemical screening, LC-MS profiling and bioactivity-guided antioxidant assays, including DPPH and hydroxyl radical scavenging methods. Preparative HPLC enabled the isolation of three compounds, among which Isolate-1 demonstrated the most potent bioactivity and was structurally characterized as Albafuran C via FTIR, NMR, and LC-MS/MS analyses. In vitro hepatoprotection studies using HepG2 cells revealed that pretreatment with Isolate-1 significantly enhanced cell viability, suppressed CCl4-induced oxidative stress, and restored antioxidant enzyme levels (SOD, CAT). Flow cytometry confirmed reduced intracellular ROS and iNOS expression, supporting its antioxidative and anti-inflammatory potential. In vivo experiments in CCl4-induced Wistar rats demonstrated significant amelioration of hepatic markers (ALT, AST, ALP, bilirubin, and albumin) and restoration of liver histoarchitecture upon treatment with Isolate-1. Molecular analysis by RT-PCR and Western blotting revealed downregulation of NF-κB signaling and inflammatory mediators. These findings confirm the hepatoprotective mechanism of V. altissima, substantiating its traditional use and identifying Albafuran C as a promising phytotherapeutic agent. This study establishes a scientific rationale for further development of Albafuran C as a natural hepatoprotective compound targeting oxidative and inflammatory liver injury.
白荆(viex altissima)是一种极具民族药理学价值的植物,被当地民间明确用作治疗肝功能疾病的传统药物。因此,本研究旨在评估树皮提取物的肝保护和抗氧化机制及其分离出的抗ccl4毒性的有效化合物。乙醇树皮提取物进行了植物化学筛选、LC-MS分析和生物活性引导的抗氧化分析,包括DPPH和羟基自由基清除方法。制备高效液相色谱法分离得到3个化合物,其中Isolate-1生物活性最强,经FTIR、NMR和LC-MS/MS分析鉴定为alafuran C。体外HepG2细胞的肝保护研究表明,用Isolate-1预处理可显著提高细胞活力,抑制ccl4诱导的氧化应激,恢复抗氧化酶(SOD, CAT)水平。流式细胞术证实细胞内ROS和iNOS表达减少,支持其抗氧化和抗炎潜力。在ccl4诱导的Wistar大鼠体内实验中,Isolate-1显著改善了肝脏标志物(ALT、AST、ALP、胆红素和白蛋白),并恢复了肝脏组织结构。RT-PCR和Western blotting分子分析显示NF-κB信号和炎症介质下调。这些发现证实了紫花苜蓿的肝保护机制,证实了其传统用途,并确定了阿伐芬C是一种有前途的植物治疗剂。本研究为进一步开发阿伐芬C作为一种针对氧化性和炎症性肝损伤的天然肝保护化合物奠定了科学基础。
{"title":"Evaluation of the hepatoprotective properties of Vitex Altissima bark extracts and isolated bioactive: In-vitro and In-vivo approach","authors":"I.A. Chethan ,&nbsp;Jaishree Vaijanathappa","doi":"10.1016/j.ejmcr.2025.100312","DOIUrl":"10.1016/j.ejmcr.2025.100312","url":null,"abstract":"<div><div><em>Vitex altissima</em> (<em>V. altissima</em>), an ethnopharmacologically valuable plant, is explicitly used as traditional medicine by local folks to cure liver-related disorders in Coorg. Hence, the present study aimed to evaluate the bark extract's hepatoprotective and antioxidant mechanisms and its isolated potent compound against CCl<sub>4</sub>-induced toxicity. Ethanolic bark extracts underwent phytochemical screening, LC-MS profiling and bioactivity-guided antioxidant assays, including DPPH and hydroxyl radical scavenging methods. Preparative HPLC enabled the isolation of three compounds, among which Isolate-1 demonstrated the most potent bioactivity and was structurally characterized as Albafuran C via FTIR, NMR, and LC-MS/MS analyses. <em>In vitro</em> hepatoprotection studies using HepG2 cells revealed that pretreatment with Isolate-1 significantly enhanced cell viability, suppressed CCl<sub>4</sub>-induced oxidative stress, and restored antioxidant enzyme levels (SOD, CAT). Flow cytometry confirmed reduced intracellular ROS and iNOS expression, supporting its antioxidative and anti-inflammatory potential. <em>In vivo</em> experiments in CCl<sub>4</sub>-induced Wistar rats demonstrated significant amelioration of hepatic markers (ALT, AST, ALP, bilirubin, and albumin) and restoration of liver histoarchitecture upon treatment with Isolate-1. Molecular analysis by RT-PCR and Western blotting revealed downregulation of NF-κB signaling and inflammatory mediators. These findings confirm the hepatoprotective mechanism of <em>V. altissima</em>, substantiating its traditional use and identifying Albafuran C as a promising phytotherapeutic agent. This study establishes a scientific rationale for further development of Albafuran C as a natural hepatoprotective compound targeting oxidative and inflammatory liver injury.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"16 ","pages":"Article 100312"},"PeriodicalIF":0.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145617527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Discovery of highly potent α-keto ester-based peptidomimetic inhibitors of the Hip1 protease for the treatment of Mycobacterium tuberculosis 发现高效α-酮酯基Hip1蛋白酶抑制剂治疗结核分枝杆菌
Pub Date : 2025-11-11 DOI: 10.1016/j.ejmcr.2025.100311
Nicholas Schumann , Farah Shamma , Cory L. Brooks , Sean J. Johnson , Matthew K. Yim , Keith J. Olsen , Karla Peña , Petros C. Karakousis , Andrew Abell , Nathan E. Goldfarb
Mycobacterium tuberculosis (Mtb), the bacterium responsible for tuberculosis, is the leading cause of death due to a single infectious agent. Given the alarming increase in drug-resistant cases, therapeutic agents targeting novel Mtb drug targets are urgently needed. Hip1, a serine protease required for Mtb survival in macrophages and tolerance to various antibiotics, has been identified as an attractive therapeutic target. In the current study, we describe the design and synthesis of highly potent (pM range Ki) peptidomimetic α-keto ester inhibitors of Hip1. We also report the first two X-ray cocrystal structures of Hip1 bound to these compounds and describe the binding interactions in the active site of recombinant Hip1. Finally, we show that these compounds effectively reduce the intracellular bacillary burden in a macrophage model of Mtb infection.
结核分枝杆菌(Mtb)是导致结核病的细菌,是由单一传染因子造成的主要死亡原因。鉴于耐药病例的惊人增长,迫切需要针对新型结核分枝杆菌药物靶点的治疗药物。Hip1是结核分枝杆菌在巨噬细胞中存活和对各种抗生素耐受所必需的丝氨酸蛋白酶,已被确定为一个有吸引力的治疗靶点。在目前的研究中,我们设计和合成了高效(pM范围Ki)的Hip1类肽α-酮酯抑制剂。我们还报道了Hip1与这些化合物结合的前两个x射线共晶结构,并描述了重组Hip1活性位点的结合相互作用。最后,我们发现这些化合物有效地减少了结核分枝杆菌感染巨噬细胞模型中的细胞内细菌负荷。
{"title":"Discovery of highly potent α-keto ester-based peptidomimetic inhibitors of the Hip1 protease for the treatment of Mycobacterium tuberculosis","authors":"Nicholas Schumann ,&nbsp;Farah Shamma ,&nbsp;Cory L. Brooks ,&nbsp;Sean J. Johnson ,&nbsp;Matthew K. Yim ,&nbsp;Keith J. Olsen ,&nbsp;Karla Peña ,&nbsp;Petros C. Karakousis ,&nbsp;Andrew Abell ,&nbsp;Nathan E. Goldfarb","doi":"10.1016/j.ejmcr.2025.100311","DOIUrl":"10.1016/j.ejmcr.2025.100311","url":null,"abstract":"<div><div><em>Mycobacterium tuberculosis</em> (Mtb), the bacterium responsible for tuberculosis, is the leading cause of death due to a single infectious agent. Given the alarming increase in drug-resistant cases, therapeutic agents targeting novel Mtb drug targets are urgently needed. Hip1, a serine protease required for Mtb survival in macrophages and tolerance to various antibiotics, has been identified as an attractive therapeutic target. In the current study, we describe the design and synthesis of highly potent (pM range <em>K</em><sub>i</sub><em>)</em> peptidomimetic α-keto ester inhibitors of Hip1. We also report the first two X-ray cocrystal structures of Hip1 bound to these compounds and describe the binding interactions in the active site of recombinant Hip1. Finally, we show that these compounds effectively reduce the intracellular bacillary burden in a macrophage model of Mtb infection.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100311"},"PeriodicalIF":0.0,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145516720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Therapeutic potential of Bowman-Birk inhibitors in various disorders: A comprehensive review Bowman-Birk抑制剂在各种疾病中的治疗潜力:综合综述
Pub Date : 2025-11-10 DOI: 10.1016/j.ejmcr.2025.100310
Masoud Hashemzaei , Majid Nimrouzi , Mehdi Salehi , Fatemeh Hosseinpour-Soleimani , Amir Tajbakhsh , Mohammad Hashem Hashempur
Bowman-Birk Inhibitors (BBIs) are plant-derived serine protease inhibitors with diverse biological activities and significant therapeutic potential. Originally isolated from soybeans, BBIs have demonstrated potent anticancer effects that surpass those of other soy-derived agents. This review comprehensively examines the multifaceted therapeutic applications of BBIs, including their anticancer, anti-inflammatory, antimicrobial, and gastrointestinal protective properties. We explore the structural and stability features and evolutionary relationships that underpin BBIs’ unique dual-inhibitory activity against serine proteases. The molecular mechanisms through which BBIs exert their effects—such as modulation of key signaling pathways, immune regulation, and microbial membrane disruption—are also discussed. Advances in synthetic peptide mimics, exemplified by sunflower trypsin inhibitor-1 (SFTI-1), highlight opportunities for therapeutic optimization. Additionally, clinical trial data on Bowman-Birk Inhibitor Concentrate (BBIC), a BBI-enriched soybean extract, demonstrate safety and efficacy without neutralizing antibody development. This review synthesizes current insights into BBIs, underscoring their remarkable versatility and promising role in cancer prevention, inflammatory disease management, and antimicrobial therapy, while addressing ongoing challenges and future directions.
Bowman-Birk抑制剂(BBIs)是植物源丝氨酸蛋白酶抑制剂,具有多种生物活性和显著的治疗潜力。BBIs最初是从大豆中分离出来的,它已经证明了比其他大豆衍生剂更有效的抗癌作用。本文综述了BBIs在多方面的治疗应用,包括其抗癌、抗炎、抗菌和胃肠道保护特性。我们探索结构和稳定性特征和进化关系,支持BBIs独特的对丝氨酸蛋白酶的双重抑制活性。通过BBIs发挥其作用的分子机制-如关键信号通路的调节,免疫调节和微生物膜破坏-也进行了讨论。合成多肽模拟物的进展,例如向日葵胰蛋白酶抑制剂-1 (SFTI-1),突出了治疗优化的机会。此外,Bowman-Birk Inhibitor Concentrate (BBIC)的临床试验数据显示,BBIC是一种富含bbi的大豆提取物,安全性和有效性不需要产生中和抗体。本综述综合了目前对BBIs的认识,强调了其在癌症预防、炎症性疾病管理和抗菌治疗方面的显著多功能性和有希望的作用,同时提出了当前的挑战和未来的方向。
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引用次数: 0
Flavonoid-mediated modulation of Tau protein: Implications for targeted therapeutics and clinical relevance in Tau-related disorders 黄酮类介导的Tau蛋白调节:Tau相关疾病的靶向治疗和临床相关性的含义
Pub Date : 2025-11-02 DOI: 10.1016/j.ejmcr.2025.100309
Rayane Hedna , Emmanuelle T. Relave , Maxime Robin , Hervé Kovacic , Gilles Breuzard
Tau protein displays a key role in promoting tubulin assembly and microtubule stabilization. Alterations in Tau expression have been implicated in many pathologies, including neurodegenerative disorders and, more recently, certain forms of cancer such as glioblastoma, where aberrant Tau expression has been reported. The exploration and development of novel Tau-targeting agents remain in a vibrant field of research due to the urgent need for effective treatments against these Tau-dependent diseases. This review focuses on flavonoids and their role in modulating Tau function. We will begin with an overview of flavonoid classes and structures. Subsequently, we examine how flavonoids influence Tau function through both direct and indirect mechanisms, alongside key pathological Tau alterations, including liquid-liquid phase separation and aggregation. Flavonoids show promise in inhibiting Tau aggregation, but their low bioavailability limits therapeutic use. In this regard, we will outline many approaches to overcome this issue through structural modifications and nano-delivery systems to improve targeting and release of flavonoids in tissue. Finally, we highlight recent advances in the rational design of Tau-targeting agents based on flavonoid scaffolds, with particular emphasis on thiazoloflavonoids explored in GBM models. Our synthesis of current knowledge positions flavonoids as a versatile chemical platform, offering a viable path for Tau-directed therapies in neurodegenerative and oncogenic contexts.
Tau蛋白在促进微管蛋白组装和微管稳定中发挥关键作用。Tau表达的改变与许多病理有关,包括神经退行性疾病,以及最近报道的某些形式的癌症,如胶质母细胞瘤,其中异常的Tau表达。由于迫切需要有效治疗这些tau依赖性疾病,探索和开发新的tau靶向药物仍然是一个充满活力的研究领域。本文就黄酮类化合物及其在Tau蛋白功能调控中的作用进行综述。我们将首先概述类黄酮的类别和结构。随后,我们研究了黄酮类化合物如何通过直接和间接机制影响Tau功能,以及关键的病理Tau改变,包括液-液相分离和聚集。黄酮类化合物显示出抑制Tau聚集的希望,但其低生物利用度限制了其治疗应用。在这方面,我们将概述许多方法来克服这一问题,通过结构修改和纳米递送系统,以提高黄酮类化合物在组织中的靶向和释放。最后,我们重点介绍了基于类黄酮支架合理设计tau靶向药物的最新进展,特别是在GBM模型中探索的噻唑类黄酮。我们目前的知识合成定位黄酮类化合物作为一个通用的化学平台,为tau定向治疗神经退行性和致癌环境提供了可行的途径。
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引用次数: 0
New promising transthyretin stabilizers for cardiac amyloidosis treatment 治疗心脏淀粉样变性的新有前途的转甲状腺素稳定剂
Pub Date : 2025-11-01 DOI: 10.1016/j.ejmcr.2025.100308
Lidia Ciccone , Caterina Camodeca , Carole Fruchart-Gaillard , Robert Thaï , Nicolò Tonali , Giuseppina Basta , Serena Del Turco , Lara Russo , Magali Noiray , Serena Sirigu , William Shepard , Lucia Barlettani , Francesco Mazzocchi , Elisabetta Orlandini , Susanna Nencetti
Transthyretin (TTR) is a plasma protein responsible for transport of thyroxine and retinol, the latter through binding with the retinol-binding protein. In contrast with its physiological role, TTR possesses an intrinsic amyloidogenic potential due to the high content of β-strands. Under pathological conditions, TTR undergoes a misfolding process forming protein aggregates and fibrils that cause organ damage and dysfunction, leading to the onset of TTR amyloidosis diseases (ATTRs). One therapeutic approach against ATTRs progression involves administering small molecules able to bind the inner channel of the protein enhancing tetramer stability. Here, we report the synthesis and characterization of 2-(((benzyloxy)imino)methyl)benzoic acids (1a-l), 3-(((benzyloxy)imino)methyl)benzoic acids (2a-l) and 4-(((benzyloxy)imino)methyl)benzoic acids (3a-l) as new potential inhibitors of TTR fibril formation. Our study shows that compounds 1a ((E)-2-((((2-(trifluoromethyl)benzyl)oxy)imino)methyl)benzoic acid)), 1d ((E)-2-((((2-chlorobenzyl)oxy)imino)methyl)benzoic acid), 2l ((E)-3-((((2-chloro-6-fluorobenzyl)oxy)imino)methyl)benzoic acid) and 3g ((E)-4-((((2-methoxybenzyl)oxy)imino)methyl)benzoic acid) effectively inhibit the aggregation of wild-type TTR (wt-TTR) and mutants (V30M, V122I). Among these derivatives 1a and 1d have stronger ability to contrast the fibril formations. The binding affinity of 1a, 1d, 2l with TTR (wt, V30M and V122I) was determined by fluorescence displacement assay and isothermal titration calorimetry. The binding modes of the selected ligands have been confirmed by X-ray crystallography. Moreover, these compounds show no toxicity in endothelial and cardiomyocyte cells, reinforcing their potential as TTR stabilizers.
转甲状腺素(TTR)是一种血浆蛋白,负责甲状腺素和视黄醇的运输,后者通过与视黄醇结合蛋白结合。与其生理作用相反,由于β-链的高含量,TTR具有内在的淀粉样蛋白形成潜能。在病理条件下,TTR发生错误折叠过程,形成蛋白聚集体和原纤维,导致器官损伤和功能障碍,导致TTR淀粉样变性病(ATTRs)的发病。针对ATTRs进展的一种治疗方法是给予能够结合蛋白质内部通道的小分子,增强四聚体的稳定性。本文报道了2-((苯氧基)亚胺基)甲基苯甲酸(1a-l)、3-((苯氧基)亚胺基)甲基苯甲酸(2a-l)和4-((苯氧基)亚胺基)甲基苯甲酸(3a-l)作为TTR纤维形成新的潜在抑制剂的合成和表征。我们的研究表明,化合物1a ((E)-2-((((2-(三氟甲基)苄基)氧(亚胺)甲基)苯甲酸))、1d ((E)-2-((((2-氯苯基)氧(亚胺)甲基)苯甲酸)、2l ((E)-3-((((2-氯-6-氟苯基)氧(亚胺)甲基)苯甲酸)和3g ((E)-4-((((2-甲氧基苄基)氧(亚胺)甲基)苯甲酸)能有效抑制野生型TTR (wt-TTR)和突变体(V30M, V122I)的聚集。其中1a和1d对原纤维形成的对比能力较强。用荧光位移法和等温滴定量热法测定了1a、1d、2l与TTR (wt、V30M和V122I)的结合亲和力。所选配体的结合模式已被x射线晶体学证实。此外,这些化合物对内皮细胞和心肌细胞没有毒性,增强了它们作为TTR稳定剂的潜力。
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European Journal of Medicinal Chemistry Reports
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